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FASEB J. 2017 Mar;31(3):1238-1247. doi: 10.1096/fj.201601132R. Epub 2016 Dec 16.

Activation of transient receptor potential vanilloid 1 by lipoxygenase metabolites depends on PKC phosphorylation.

Author information

1
Institute for Drug Research, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
2
Institute for Drug Research, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel avip@ekmd.huji.ac.il.

Abstract

Peripheral neuronal activation by inflammatory mediators is a multifaceted physiological response that involves a multitude of regulated cellular functions. One key pathway that has been shown to be involved in inflammatory pain is Gq/GPCR, whose activation by inflammatory mediators is followed by the regulated response of the cation channel transient receptor potential vanilloid 1 (TRPV1). However, the mechanism that underlies TRPV1 activation downstream of the Gq/GPCR pathway has yet to be fully defined. In this study, we employ pharmacological and molecular biology tools to dissect this activation mechanism via perforated-patch recordings and calcium imaging of both neurons and a heterologous system. We showed that TRPV1 activity downstream of Gq/GPCR activation only produced a subdued current, which was noticeably different from the robust current that is typical of TRPV1 activation by exogenous stimuli. Moreover, we specifically demonstrated that 2 pathways downstream of Gq/GPCR signaling, namely endovanilloid production by lipoxygenases and channel phosphorylation by PKC, converge on TRPV1 to evoke a tightly regulated response. Of importance, we show that only when both pathways are acting on TRPV1 is the inflammatory-mediated response achieved. We propose that the requirement of multiple signaling events allows subdued TRPV1 activation to evoke regulated neuronal response during inflammation.-Kumar R., Hazan, A., Geron, M., Steinberg, R., Livni, L., Matzner, H., Priel, A. Activation of transient receptor potential vanilloid 1 by lipoxygenase metabolites depends on PKC phosphorylation.

KEYWORDS:

Gq-GPCR; TRP channels; eicosanoids; endovanilloids; inflammatory pain

PMID:
27986808
DOI:
10.1096/fj.201601132R
[Indexed for MEDLINE]

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